Anxiety disorder has main symptoms such as panic, uneasy and repeated anxieties, and patients under mental disorder state cannot exert normal living ability and effectively work, and long-term of diseases may grievously influence patients' health and daily life, and even may induce more serious consequences such as suicide. In addition, the later phase of anxiety is usually accompanied with depression symptoms. Some statistical results show that the patients with anxiety are of 8-13% of the world population, and most of them are lack of necessary medicinal intervention and treatment. Hence, it is very important to develop medicaments with good activity against anxiety and depression.
Traditional drugs such as diazepam, alpidem are widely used in clinic for treatment of anxiety and depression, but these previous drugs can not only act on peripheral benzodiazepine receptor (PBR), but also act on central benzodiazepine receptor (CBR), so that they may frequently induce side effects such as sedation, hypnosis, amnesia, muscle relaxation, tolerance, and may easily induce drug dependence and addiction. Thus, it is urgent to have anxiolytics drugs with higher target specificity, less side effects and lower drug dependence.
Some researches show that PBR is mainly on cell mitochondrial membrane, and is one of pivotal components of cell mitochondrial membrane receptor complex, and thus is also called as mitochondrial benzodiazepine receptor (MBR). The whole structure of the receptor complex comprises a translocator protein 18 KDa (TSPO) located at mitochondrial outer membrane, and TSPO as the minimum functional unit of PBR/MBR can combine with pharmaceutical ligand and cholesterol and exert important functions (Trends Pharmacol Sci, 2006, 27(8): 402-409; J Med Chem, 2009, 52(3): 581-592.).
TSPO has potential value in treatment of anxiety. After TSPO combines with corresponding ligand, it can promote the entrance of cholesterol into mitochondria, and stimulate biosynthesis of neurosteroids, while neurosteroids can act on GABA-A receptor and produce anxiolytic effects, but do not produce apparent side effects.
At present, TSPO ligands are very widely studied, and it has been reported that many compounds exert good activity in vivo and in vitro, and TSPO ligands having relatively high affinity and selectivity are reported as well. According to their chemical structure, there are mainly benzodiazepines (e.g., 4′-chlorodiazepam (Ro5-4864)], isoquinoline amides, benzothiazepines, benzoxazepines, indole acetamides (e.g., FGIN), imidazopyridine acetamides, aryloxyaniline derivatives, pyrazolopyrimidine acetamides, 3-indolyloxamides, 2-arylpyrimidine derivatives, and 2-aryl-8-oxypurine derivatives. These ligands have roughly same basic structure, and can be concluded as: containing one hydrogen bond donator (δ1, usually amide), two lipophilic areas (PAR and FRA) on mother ring backbone, and another lipophilic area (LA) binding to receptor via allosterism (Curr Med Chem, 2006, 13(17): 1991-2001; Curr Med Chem, 2009, 16(26): 3359-3380.).
In corresponding animal models and clinical studies, some of the selective TSPO ligands had been showed potential values in creating new drugs with TSPO as target. For example, PK11195, a TSPO/PBR selective antagonist, has been widely used in finding new types of TSPO ligands and activity comparison as a tool drug. In addition, Emapunil (AC-5216, XBD173) has high selectivity and affinity, less side effects, no remarkable withdrawal symptoms and drug withdraw rebounding symptoms, and thus enters phase II clinical research (Science 2009, 325, 490-195; Prog Neuro-Psychoph, 2009, 33, 1040-1045.). However, most of these compounds have poor pharmacokinetics, low bioavailability, difficulty in penetrating blood brain barrier. Hence, it is still needed to find better TSPO ligands.